Recent advances in computer aided drug design, medicinal chemistry, molecular biology, synthetic chemistry and related technologies provide unprecedented opportunities to develop new approaches and insights into health and disease. The long term goals of this multidisciplinary research are to develop more systematic, rational approaches to the design of potent receptor/acceptor selective peptide and peptidomimetic ligands for hormone and neurotransmitter receptors. We seek to obtain a fundamental understanding of the chemical/physical basis for information transfer by peptide hormones and neurotransmitters and how these chemical messengers modulate and control cellular function. This understanding is critical to the development of effective drugs with little or no toxic side effects. The development and use of methods for conformational and the topographical constraints compatible with high potency and receptor selectivity are of critical importance to this research. This research requires a highly multidisciplinary approach including computer assisted modeling, conformational analysis using 2D NMR spectroscopy and other biophysical methods, asymmetric synthetic methods, macrocyclic peptide and peptidomimetic synthetic methods, evaluation of conformation- biological activity relationships, and utilization of cloned receptors to obtain potent, receptor selective peptides and peptidomimetics with specific biological properties. The primary focus of this research will be on design of potent and selective agonists and antagonists. Specific aims include: 1) to design, synthesize and develop novel amino acids, amino acid mimetics, peptide and non-peptide scaffolds that can lead to novel agonists and antagonists for the recently discovered human melanocortin receptors (MC1R, MC3R, MC4R and MC5R); 2) to follow-up novel leads to obtain highly potent and receptor selective agonist and antagonist ligands for these receptors; 3) to evaluate specific pharmacophore hypotheses regarding the structural, conformational and topographical requirements for ligands for the melanocortin and oxytocin receptors; 4) to develop non-peptide templates for melanotropin peptidomimetics; 5) to utilize cell lines which specifically contain the hMC1R, hMC3R, hMC4R and hMC5R to examine binding affinity and second messenger activity for our novel ligands;6) to continue to utilize and develop biophysical methods to examine the conformational, topographical and dynamic properties of selected ligand with unique biological profiles; 7) to effectively collaborate with our biological and biophysical colleagues to obtain novel insights into the biological roles of melanocortin and oxytocin receptors and ligands in health and disease.